AXL is a class of receptor tyrosine kinase and belongs to the TAM receptor tyrosine kinase family which also includes two other members: Mer and Tyro3. TAM was first found in tumor cells, and its overexpression and ectopic expression are closely related to immune regulation, tumor proliferation, growth and migration, etc. AXL was isolated in 1988 from patients with chronic myeloid leukemia and chronic myeloproliferative disorders. AXL is widely expressed in the brain, immune cells, platelets, endothelial cells, skeletal muscle, heart, liver, kidney and other tissues. Vitamin K-dependent protein kinase Gas6 (growth arrest-specific 6) is the most widely studied AXL ligand currently discovered, and the other ligands of the TAM family include Protein S, Tubby, Tulp-1 and Galectin-3. The TAM family share a similar protein structure, which is mainly comprised of three parts, namely, an extracellular domain, a transmembrane region and an intracellular domain, wherein the extracellular domain includes two Igs at the N-terminal immunoglobulin-like region, and two fibronectin III repeat fragments (FNIII). Gas6 binds to the extracellular domain of AXL and then induces the dimerization of AXL, triggering the trans-autophosphorylation of the intracellular domain, and thereby activating intracellular signaling pathways and regulating a series of physiological activities, such as the regulation of cell growth and proliferation through the Src/MAPK/ERK pathway; the stimulation of the expression of anti-apoptotic proteins through the PI3K/AKT pathway; and the regulation of cell migration and proliferation through the PI3K/p38/MAPK pathway. In addition to Gas6-dependent activation, AXL can also be activated in a ligand-independent manner. AXL is involved in the adhesion and immunomodulatory effects of normal cells, and studies have found that the overexpression of AXL occurs in a variety of tumor cells, and Gas6/AXL-regulated signaling pathways are closely related to the occurrence and development of a variety of tumors, such as chronic myelocytic leukemia, breast cancer, prostate cancer, non-small cell lung cancer, pancreatic cancer, melanoma, glioma and renal cell carcinoma. It has been demonstrated that inhibiting the expression of AXL can reduce the proliferation and growth of pancreatic cancer cells, and inhibit the invasion and migration of breast cancer cells. In non-small cell lung cancer, gene-silencing AXL can inhibit tumor growth. Furthermore, the high expression of AXL is also associated with tumor recurrence and tolerance of other anticancer drugs, such as Gliver, Tarceva, and Tyverb. These evidences indicate that AXL is a valid target for tumor targeting therapy.
Bosutinib (SKI606, PF5208763, Bosulif; Pfizer, 2012), Cabozantinib (XL184, Cometriq; Exelixis, 2012), Sunitinib (SUl11248, Sutent; Pfizer, 2006) and other marketed drugs, though having AXL activity, are multi-targeted drugs with no specificity. BGB324 (R428; Rigel Pharmaceuticals, BergenBio) is a small molecule inhibitor against AXL with the highest specificity known so far in the market and is being under the first clinical trial, and in December 2014, the FDA awarded BGB324 the title of orphan drug for treating AML. At present, no small molecule inhibitor against AXL kinase has yet been available in the market.